Alectinib Versus Crizotinib in Asian Patients With Treatment-Naïve Advanced ALK-Positive NSCLC: Five-Year Update From the Phase 3 ALESIA Study

Introduction Previous results from the phase 3 ALESIA study (NCT02838420) revealed that alectinib (a central nervous system [CNS]-active, ALK inhibitor) had clinical benefits in treatment-naïve Asian patients with advanced ALK-positive NSCLC, consistent with the global ALEX study. We present updated data after more than or equal to 5 years of follow-up from the “last patient in” date. Methods Adult patients with treatment-naïve, advanced ALK-positive NSCLC from mainland China, South Korea, and Thailand were randomized 2:1 to receive twice-daily 600 mg alectinib (n = 125) or 250 mg crizotinib (n = 62). The primary endpoint was investigator-assessed progression-free survival. Secondary or exploratory endpoints included overall survival, objective response rate, time to CNS progression, and safety. Results At the data cutoff (May 16, 2022), the median survival follow-up was 61 and 51 months in the alectinib and crizotinib arms, respectively. Median progression-free survival was 41.6 months with alectinib versus 11.1 months with crizotinib (stratified hazard ratio = 0.33, 95% confidence interval: 0.23–0.49). Overall survival data remain immature; 5-year overall survival rates were 66.4% (alectinib arm) versus 56.1% (crizotinib arm). Objective response rate was 91.2% versus 77.4% with alectinib and crizotinib, respectively. CNS progression was delayed with alectinib versus crizotinib (cause-specific hazard ratio = 0.16, 95% confidence interval: 0.08–0.32). Median treatment duration was longer with alectinib versus crizotinib (42.3 versus 12.6 mo). No new safety signals were observed. Conclusions With four additional years of follow-up, these updated results confirm the clinical benefit and manageable safety of alectinib in Asian patients with advanced ALK-positive NSCLC, and confirm alectinib as a standard-of-care treatment for patients with advanced ALK-positive NSCLC.


Introduction
More than 50% of lung cancer cases worldwide are recorded in Asia, where 21% of cancer deaths occur owing to lung cancer. 1 This highlights the need for improved treatment strategies in Asian patients.][3] Alectinib was approved for the treatment of ALKpositive NSCLC in Japan at a dose of 300 mg twice daily on the basis of results of the single-arm phase 1-2 AF-001JP study (JapicCTI-101264) in ALK inhibitor-naïve Japanese patients. 4Confirmatory data were provided by the randomized phase 3 J-ALEX study (JapicCTI-132316), which compared the efficacy and safety of 300 mg twice-daily alectinib with 250 mg twice-daily crizotinib in ALK inhibitor-naïve Japanese patients with ALK-positive NSCLC, who were chemotherapy naïve or who had received one previous chemotherapy regimen.Treatment crossover between arms was permitted following study drug discontinuation. 5Final progression-free survival (PFS) data from J-ALEX demonstrated superiority in independent review facilityassessed median PFS in patients who received alectinib (n ¼ 103; 34.1 mo, 95% confidence interval [CI]: 22.1not estimable [NE]) versus crizotinib (n ¼ 104; 10.2 mo, 95% CI: 8.3-12.0)with a hazard ratio (HR) of 0.37 (95% CI: 0.26-0.52]). 6However, final overall survival (OS) data from J-ALEX did not reveal superiority of alectinib over crizotinib; median OS was not reached (NR) in either treatment arm (alectinib arm: 95% CI: 70.6-NE; crizotinib arm: 95% CI: 68.5-NE; HR ¼ 1.03, 95% CI: 0.67-1.58),and the 5-year OS rate was 60.9% (95% CI: 51.4-70.3)with alectinib and 64.1% (95% CI: 54.9-73.4) with crizotinib. 7n the USA and Europe, alectinib was approved as a first-line treatment for patients with ALK-positive NSCLC on the basis of data from the global randomized phase 3 ALEX study (NCT02075840), which compared the efficacy and safety of alectinib at 600 mg versus crizotinib at 250 mg, twice daily, in treatment-naïve patients with advanced ALK-positive NSCLC. 8At the primary analysis of ALEX, investigator-assessed PFS was significantly longer in patients treated with alectinib versus crizotinib: median PFS was NE (95% CI: 17.7-NE) in the alectinib arm versus 11.1 months (95% CI: 9.1-13.1) in the crizotinib arm (HR ¼ 0.47, 95% CI: 0.34-0.65,p < 0.001). 8Mature PFS data from ALEX confirmed a significant improvement in investigator-assessed median PFS for alectinib (34.8 mo, 95% CI: 17.7-NE) relative to crizotinib (10.9 mo, 95% CI: 9.1-12.9),with a HR of 0.43 (95% CI: 0.32-0.58). 9Of note, OS data from ALEX were immature at the updated analysis, with only 37% of patients having events (stratified HR ¼ 0.67, 95% CI: 0.46-0.98);median OS was NE in the alectinib arm versus 57.4 months (95% CI: 34.6-NE) in the crizotinib arm.Despite this immaturity of the OS data, a clinically meaningful improvement in the 5-year OS rate was reported with alectinib (62.5%, 95% CI: 54.3-70.8)versus crizotinib (45.5%, 95% CI: 33.6-57.4). 9 Finally, alectinib also revealed intracranial activity; a CNS response occurred in 17 out of 21 patients with CNS metastases in the alectinib arm (CNS response rate, 81%; 95% CI: 58-95), and in 11 out of 22 patients with CNS metastases in the crizotinib arm (CNS response rate, 50%; 95% CI: 28-72). 8n the randomized phase 3 ALESIA study (NCT02838420), treatment-naïve Asian patients with advanced ALK-positive NSCLC were enrolled to receive the globally approved 600 mg twice-daily alectinib dose; the primary objective was to assess whether the PFS benefit of alectinib in this patient population was consistent with that observed in the global ALEX study.In the primary analysis of ALESIA (data cutoff: May 31, 2018), comprising 125 patients in the alectinib arm and 62 patients in the crizotinib arm, the PFS benefit of alectinib versus crizotinib observed in ALEX was revealed in Asian patients with advanced ALK-positive NSCLC 10 : investigator-assessed PFS was significantly prolonged with alectinib versus crizotinib (median PFS NE [95% CI: 20.3-NE] versus 11.1 mo [95% CI: 9.1-13.0],respectively; HR ¼ 0.22, 95% CI: 0.13-0.38,p < 0.0001).The favorable efficacy of alectinib was consistently observed across secondary endpoints, including independent review committee (IRC)-assessed time to CNS progression. 10Here, we report updated data from ALESIA (data cutoff: May 16, 2022), with a follow-up of more than or equal to 5 years from the date of the last patient in.

Study Design
Full study details have been described previously. 10riefly, the intent-to-treat (ITT) population, defined as all randomized patients, comprised Asian patients aged more than or equal to 18 years with previously untreated, stage IIIB or IV ALK-positive NSCLC, who were enrolled from 21 sites in mainland China, South Korea, and Thailand.Eligibility criteria included an Eastern Cooperative Oncology Group performance status of 0 to 2, measurable baseline disease per Response Evaluation Criteria in Solid Tumors v1.1, and a life expectancy of more than or equal to 12 weeks.Patients with asymptomatic brain metastases were eligible; those with asymptomatic progressive disease (PD) in the CNS could receive localized treatment and continue with the study treatment until systemic PD or symptomatic PD in the CNS.
Patients were randomized 2:1 to receive either alectinib 600 mg orally or crizotinib 250 mg orally, twice daily, until PD, unacceptable toxicity, consent withdrawal, or death.Randomization was performed centrally by means of an interactive voice or web response system and was stratified by Eastern Cooperative Oncology Group performance status (0 or 1 versus 2) and baseline CNS metastases (yes versus no).Although treatment crossover between study arms was not permitted, patients could receive any available treatment after discontinuation from study treatment.
The study was conducted in accordance with the principles of the Declaration of Helsinki, the International Council for Harmonization guidelines for Good Clinical Practice, and country-specific laws and regulations.The study protocol was reviewed by the institutional review board.All patients provided written informed consent.

Endpoints and Assessments
All patients had regular tumor imaging, including brain magnetic resonance imaging, at baseline and every 8 weeks until PD; responses were evaluated using Response Evaluation Criteria in Solid Tumors v1.1.The primary endpoint was investigator-assessed PFS.Secondary endpoints included IRC-assessed PFS, IRCassessed time to CNS progression, objective response rate, duration of response, OS, and safety.Endpoints that were assessed by the IRC were only undertaken for the primary analysis; investigator-assessed time to CNS progression was included as an exploratory endpoint in this updated analysis instead.Adverse events (AEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0.

Statistical Analyses
The primary objective of the ALESIA study was to determine whether the investigator-assessed PFS benefit with alectinib was consistent with the benefit reported in the global ALEX trial.Consistency was defined as maintaining greater than or equal to 50% of risk reduction from ALEX (i.e., as the HR for investigatorassessed PFS for ALEX was 0.47 [53% risk reduction], if the point estimate of the HR from ALESIA was less than 0.735, then the primary objective to determine consistency would be met).
Kaplan-Meier methodology was used to estimate time-to-event endpoints for each treatment arm with corresponding 95% CI, and a stratified Cox regression model using the stratification factors for randomization was used to estimate the HR and 95% CI of the treatment effect.The Clopper-Pearson method was used to estimate the proportion of patients who achieved an objective response with corresponding 95% CI, and proportions of responses were compared using a Mantel-Haenszel test on the basis of the stratification factors.Non-CNS progression without previous CNS progression, and death without previous CNS or non-CNS progression, were regarded as competing risks for CNS progression; therefore, HRs were calculated on the basis of cause-specific hazard functions to account for competing risks in the time to CNS progression analysis.The probability of CNS disease progression, non-CNS disease progression, and death were each estimated with the use of cumulative incidence functions.The p values presented for the efficacy endpoints are descriptive only.

Patients
Baseline characteristics of the ITT population have been described previously. 10Briefly, between August 3, 2016, and May 16, 2017, 187 patients were randomized to receive alectinib (n ¼ 125) or crizotinib (n ¼ 62).Baseline patient characteristics of the ITT population were generally balanced between the treatment arms, as described previously (Supplementary Table 1). 10In total, IRC-assessed baseline CNS metastases were present in 44 patients in the alectinib arm and 23 patients in the crizotinib arm.
Grade 3 to 5 AEs with the greatest difference in incidence rate between alectinib and crizotinib were neutrophil count decrease (0.0% versus 14.5%, respectively) and weight increase (8.8% versus 1.6%, respectively) (Supplementary Table 2).The grade 3 to 5 TRAEs with the largest difference in incidence rate between the alectinib and crizotinib arms were neutrophil count decrease (alectinib 0.0% versus crizotinib 14.5%) and alanine aminotransferase increase (alectinib 1.6% versus crizotinib 6.5%) (Supplementary Table 3).Three fatal AEs occurred after the primary analysis in the alectinib arm (two patients died of unknown causes and one patient died owing to coronavirus disease 2019 pneumonia); these were considered unrelated to the study treatment.

Discussion
After at least 5 years of follow-up, investigatorassessed PFS in the ALESIA study was consistent with the primary analysis results. 10 Investigator-assessed median PFS was prolonged with alectinib (41.6 mo, 95% CI: 33.1-58.9)versus crizotinib (11.1 mo, 95% CI: 9.1-18.4)(HR ¼ 0.33, 95% CI: 0.23-0.49).These updated data support the clinical benefit observed with alectinib versus crizotinib in patients with advanced ALK-positive NSCLC in the randomized phase 3 ALEX and J-ALEX studies. 5,6,8,9tably, PFS was improved with alectinib versus crizotinib in both patients with and without baseline CNS metastases, with a larger improvement observed in patients with baseline CNS disease.In addition, the cumulative incidence of CNS progression was consistently lower over time with alectinib compared with crizotinib, suggesting that alectinib helps to control and prevent CNS disease in this patient population.These results are consistent with the CNS-protective effects of alectinib as described previously in patients with ALK-positive NSCLC; in the ALEX study, the time to CNS progression was significantly longer with alectinib versus crizotinib (cause-specific HR ¼ 0.16, 95% CI: 0.10-0.28,p < 0.001); 12% (18 of 152) of alectinib-treated patients and 45% (68 of 151) of crizotinib-treated patients had a CNS progression event) demonstrating that treatment with alectinib reduces the risk of CNS progression in patients with ALK-positive NSCLC. 11edian OS was NE in either treatment arm (alectinib arm: 95% CI: NE-NE; crizotinib arm: 95% CI: 45.5-NE) and the stratified OS HR (HR ¼ 0.60, 95% CI: 0.37-0.99)was in line with findings from the 5-year OS analysis of ALEX (HR ¼ 0.67, 95% CI: 0.46-0.98). 9A clinically meaningful difference in survival duration was observed, with a 5-year OS rate of 66.4% (95% CI: 57.9-74.9)with alectinib versus 56.1% (95% CI: 43.0-69.1)with crizotinib.
A lower proportion of patients with PD (including symptomatic deterioration) were reported to have received subsequent anti-cancer therapy after alectinib (61.8%) than after crizotinib (79.2%).As seen in the ALEX study, ALK inhibitors were the most common postprogression therapy in both arms of ALESIA, although a lower proportion of patients with PD received an ALK  inhibitor following alectinib (36.8%) than following crizotinib (58.3%); however, this was not seen for those who received post-progression chemotherapy (alectinib arm: 35.3%; crizotinib arm: 31.3%). 9This difference may be due to there being limited approved and experimental ALK inhibitors for patients with PD following alectinib treatment versus crizotinib treatment, and due to missing data on subsequent anti-cancer therapy for patients who were lost to follow-up.
In this long-term safety update from ALESIA, a favorable safety profile for alectinib relative to crizotinib was observed, despite a three-times longer duration of alectinib treatment.The most frequently reported AEs in this updated analysis were generally consistent with the primary analysis. 10However, the rate of serious AEs in the alectinib arm increased from the primary analysis (28.0% versus 15.0%), which may be owing to the longer duration of alectinib treatment. 10Nevertheless, the newly reported serious AEs were consistent with the known safety profile of alectinib, and incidence rates of serious AEs were still comparable between arms (28.0% with alectinib versus 29.0% with crizotinib).Newly reported grade 3 to 5 AEs were consistent with the known safety profile of alectinib.
The limitations of this analysis include the open-label study design which may have biased the results, as previously discussed, although the primary analysis of ALESIA used IRC assessments to mitigate this. 10 Due to the dosage difference between alectinib and crizotinib (with four capsules being required for alectinib versus one for crizotinib), an open-label study was necessary to prevent increasing patient and overall study burden.In addition, OS data remain immature.
Previous studies have investigated the efficacy and safety of other ALK inhibitors, such as ceritinib, brigatinib, and lorlatinib in patients with advanced ALK-positive NSCLC [12][13][14] ; cross-study comparisons should be interpreted with caution, owing to differences in study design, and populations.In the ALTA-1 study, 13 patients who received brigatinib had a higher investigator-assessed median PFS (30.8 mo, 95% CI: 21.3-40.6)than patients who received crizotinib (9.2 mo, 95% CI: 7.4-12.7);median OS was NR in either treatment arm.Compared with crizotinib, brigatinib reduced the risk of intracranial progression by 71% in patients who had baseline brain metastases (HR ¼ 0.29, 95% CI: 0.17-0.51).Higher rates of grade 3 AEs, dose reductions, and discontinuations were reported in patients who received brigatinib versus crizotinib. 13In the phase 3 CROWN study, 14 median investigator-assessed PFS were NR (95% CI: NR-NR) with lorlatinib versus 9.1 months (95% CI: 7.4-10.9)with crizotinib.Lorlatinib was associated with a longer time to intracranial progression than crizotinib in patients with baseline brain metastases (HR ¼ 0.10, 95% CI: 0.04-0.27).Higher rates of grade 3 to 4 AEs were reported in the lorlatinib arm compared with the crizotinib arm (76% versus 57%, respectively); 7% and 10% of patients in these two arms discontinued treatment owing to AEs. 14 However, updated data from this study are consistent with ALEX and confirm alectinib as a standard-of-care treatment option for advanced ALK-positive NSCLC.

Conclusions
Updated efficacy and safety results from ALESIA after more than or equal to 5 years of follow-up are consistent with the primary analysis, and with data from the global ALEX study, supporting the finding that 600 mg twice-daily alectinib is effective and well tolerated as a first-line treatment for patients with advanced ALK-positive NSCLC.The mature investigator-assessed PFS confirmed the systemic and CNS efficacy of alectinib versus crizotinib in Asian patients with previously untreated ALK-positive NSCLC.In addition, a clinically meaningful difference in OS was seen between the treatment arms in favor of alectinib, and a consistently lower CIR for CNS progression was also observed with alectinib versus crizotinib.Despite the longer duration of treatment in the alectinib versus the crizotinib arm, the updated safety data were still in favor of alectinib, and no new safety concerns were observed.
In conclusion, the clinical benefit observed after more than or equal to 5 years of follow-up, coupled with a tolerable and manageable safety profile, confirms alectinib as the standard-of-care treatment for patients with advanced ALK-positive NSCLC.

Figure 2 .Figure 3 .
Figure2.Updated OS (A) in the ITT population, and (B) in patients with and without CNS metastases at baseline.CI, confidence interval; CNS, central nervous system; HR, hazard ratio; ITT, intent-to-treat; mOS, median overall survival; NE, not estimable; OS, overall survival.

125) Alectinib better Crizotinib better Crizotinib (n = 62) Baseline risk factors
A B C Figure 1.Updated investigator-assessed PFS (A) in the ITT population, (B) in patients with and without CNS metastases at baseline, and (C) in prespecified patient subgroups.CI, confidence interval; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; INV, investigator; ITT, intent-to-treat; mPFS, median progression-free survival; PFS, progression-free survival.

Table 1 .
Subsequent Anti-Cancer Therapy in Patients From the Alectinib Arm and the Crizotinib Arm, Following Disease Progression While on Study Treatment

Table 3 .
Adverse Events With Greater Than or Equal to 10% Difference in Frequency Between the Treatment Arms